I am proposing to study the regulation of the handling of glucose by the isolated, blood perfused canine liver. The liver is extirpated from a beagle puppy, and perfused in vitro with venous and arterial blood drawn from a large support dog. Hepatic venous effluent from the perfused organ is automatically returned to the support dog. Hepatic arterial, portal venous, and hepatic venous blood flows are measured automatically, and samples of blood at three ports are taken. It is thus possible to measure the time course of the net hepatic glucose balance during infusions of substances into the portal vein inflow to the liver. Biopsy samples of the liver are collected at various times for the determination of glycogen, and by infusing C14-glucose or H3-3-glucose it will be possible to determine the rate of production of new glucose and absolute glucose utilization rate by the liver. The relative effects of various temporal patterns of glucose alone, insulin alone, and glucose plus insulin on the net hepatic glucose balance, net rate of glycogen deposition, and the absolute rates of hepatic glucose production and utilization will be determined. The results obtained will be used to evolve a computer simulation of the liver's dynamic responses to the infusion of glucose and insulin. In a second series of studies the quantitative role of the pancreas in the regulation of hepatic glucose handling will be examined. Using the isolated, blood perfused pancreas, the response of pancreatic glucagon secretion to glucose and amino acids will be observed, a mathematical simulation of the pancreas will be developed, and by coupling the mathematical description of the pancreas with that of the liver a systematic, dynamic prediction of how the organs function in series will result. The prediction will then be tested by perfusing the pancreas and liver in series, and determining the net hepatic glucose balance of the coupled system in the absence of stimulation, and during glucose and insulin infusions.